Genome-wide association study of varenicline-aided smoking cessation.

Introduction: Varenicline is an α4β2 nicotinic acetylcholine receptor partial agonist with the highest therapeutic efficacy of any pharmacological smoking cessation aid and a 12-month cessation rate of 26%. Genetic variation may be associated with varenicline response, but to date no genome-wide association studies of varenicline response have been published.

Methods: In this study, we investigated the genetic contribution to varenicline effectiveness using two electronic health record-derived phenotypes.

Common and Distinct Genetic Architecture of Age at Diagnosis of Diabetes in South Indian and European Populations.

Objective: South Asians are diagnosed with type 2 diabetes (T2D) more than a decade earlier in life than seen in European populations. We hypothesized that studying the genomics of age of diagnosis in these populations may give insight into the earlier age diagnosis of T2D among individuals of South Asian descent.

Research Design And Methods: We conducted a meta-analysis of genome-wide association studies (GWAS) of age at diagnosis of T2D in 34,001 individuals from four independent cohorts of European and South Asian Indians.

A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance.

Background And Aims: The efficacy of statin therapy is hindered by intolerance to the therapy, leading to discontinuation. Variants in SLCO1B1, which encodes the hepatic transporter OATB1B1, influence statin pharmacokinetics, resulting in altered plasma concentrations of the drug and its metabolites. Current pharmacogenetic guidelines require sequencing of the SLCO1B1 gene, which is more expensive and less accessible than genotyping.

Assessment of metal contaminants along the Bay of Bengal - Multivariate pollution indices.

The spatial concentration of heavy metals (Mn, Ni, Cu, Co, Zn, Cd, and Pb) was studied in coastal areas (n = 9) including water (n = 27) and sediment (n = 27) in the Palk Bay, India to understand the metal pollution due to prevailing natural and anthropogenic activities. Pollution indices like metal index (MI), geoaccumulation index (Igeo), contamination factor (CF), pollution load index (PLI) and potential ecological risk (PER) were calculated based on the background/reference value. The values of MI index indicated that water was free of metals, whereas Igeo, CF, PLI and PER indicated moderate contamination of sediment in monsoon.

Identification of 4 New Loci Associated With Primary Hyperparathyroidism (PHPT) and a Polygenic Risk Score for PHPT.

Context: A hypothesis-free genetic association analysis has not been reported for patients with primary hyperparathyroidism (PHPT).

Objective: We aimed to investigate genetic associations with PHPT using both genome-wide association study (GWAS) and candidate gene approaches.

Methods: A cross-sectional study was conducted among patients of European White ethnicity recruited in Tayside (Scotland, UK).

Young-onset diabetes in Asian Indians is associated with lower measured and genetically determined beta cell function.

Aims/hypothesis: South Asians in general, and Asian Indians in particular, have higher risk of type 2 diabetes compared with white Europeans, and a younger age of onset. The reasons for the younger age of onset in relation to obesity, beta cell function and insulin sensitivity are under-explored.

Methods: Two cohorts of Asian Indians, the ICMR-INDIAB cohort (Indian Council of Medical Research-India Diabetes Study) and the DMDSC cohort (Dr Mohan's Diabetes Specialties Centre), and one of white Europeans, the ESDC (East Scotland Diabetes Cohort), were used.

LTA4H rs2660845 association with montelukast response in early and late-onset asthma.

Leukotrienes play a central pathophysiological role in both paediatric and adult asthma. However, 35% to 78% of asthmatics do not respond to leukotriene inhibitors. In this study we tested the role of the LTA4H regulatory variant rs2660845 and age of asthma onset in response to montelukast in ethnically diverse populations.

A cell type-specific transcriptomic approach to map B cell and monocyte type I interferon-linked pathogenic signatures in Multiple Sclerosis.

Alteration in endogenous Interferon (IFN) system may profoundly impact immune cell function in autoimmune diseases. Here, we provide evidence that dysregulation in IFN-regulated genes and pathways are involved in B cell- and monocyte-driven pathogenic contribution to Multiple Sclerosis (MS) development and maintenance. In particular, by using an Interferome-based cell type-specific approach, we characterized an increased susceptibility to an IFN-linked caspase-3 dependent apoptotic cell death in both B cells and monocytes of MS patients that may arise from their chronic activation and persistent stimulation by activated T cells.

Author Correction: Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Neural precursor cell-secreted TGF-β2 redirects inflammatory monocyte-derived cells in CNS autoimmunity.

In multiple sclerosis, the pathological interaction between autoreactive Th cells and mononuclear phagocytes in the CNS drives initiation and maintenance of chronic neuroinflammation. Here, we found that intrathecal transplantation of neural stem/precursor cells (NPCs) in mice with experimental autoimmune encephalomyelitis (EAE) impairs the accumulation of inflammatory monocyte-derived cells (MCs) in the CNS, leading to improved clinical outcome. Secretion of IL-23, IL-1, and TNF-α, the cytokines required for terminal differentiation of Th cells, decreased in the CNS of NPC-treated mice, consequently inhibiting the induction of GM-CSF-producing pathogenic Th cells.

Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis.

Recent evidence indicates that single multiple sclerosis (MS) susceptibility genes involved in interferon (IFN) signaling display altered transcript levels in peripheral blood of untreated MS subjects, suggesting that responsiveness to endogenous IFN is dysregulated during neuroinflammation. To prove this hypothesis we exploited the systematic collection of IFN regulated genes (IRG) provided by the Interferome database and mapped Interferome changes in experimental and human MS. Indeed, central nervous system tissue and encephalitogenic CD4 T cells during experimental autoimmune encephalomyelitis were characterized by massive changes in Interferome transcription.

Biomechanical considerations for assessing interactions of children and small occupants with inflatable seat belts.

NHTSA estimates that more than half of the lives saved (168,524) in car crashes between 1960 and 2002 were due to the use of seat belts. Nevertheless, while seat belts are vital to occupant crash protection, safety researchers continue efforts to further enhance the capability of seat belts in reducing injury and fatality risk in automotive crashes. Examples of seat belt design concepts that have been investigated by researchers include inflatable, 4-point, and reverse geometry seat belts.

Biomechanical assessment of a rear-seat inflatable seatbelt in frontal impacts.

This study evaluated the biomechanical performance of a rear-seat inflatable seatbelt system and compared it to that of a 3-point seatbelt system, which has a long history of good real-world performance. Frontal-impact sled tests were conducted with Hybrid III anthropomorphic test devices (ATDs) and with post mortem human subjects (PMHS) using both restraint systems and a generic rear-seat configuration. Results from these tests demonstrated: a) reduction in forward head excursion with the inflatable seatbelt system when compared to that of a 3-point seatbelt and; b) a reduction in ATD and PMHS peak chest deflections and the number of PMHS rib fractures with the inflatable seatbelt system and c) a reduction in PMHS cervical-spine injuries, due to the interaction of the chin with the inflated shoulder belt.

QSAR studies on N-aryl derivative activity towards Alzheimer's disease.

A Quantitative Structure Activity Relationship (QSAR) study has been an attempted on a series of 88 N-aryl derivatives which display varied inhibitory activity towards both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), targets in Alzheimer's drug discovery. QSAR models were derived for 53 and 61 compounds for each target, respectively, with the aid of genetic function approximation (GFA) technique using topological, molecular shape, electronic and structural descriptors. The predictive ability of the QSAR model was evaluated using a test set of 26 compounds for AChE (r(2)(pred) = 0.